Synthesis of boronate ester derivatives and uses thereof

Abstract

Disclosed herein are methods for the preparation of boronate derivatives in the synthesis of antimicrobial compounds and uses thereof. Disclosed herein includes method of making a compound of Formula (B) by reducing the ketone group of the keto-ester compound of Formula (A), and the reduction can be performed using a Ruthenium based catalyst system or using an alcohol dehydrogenase bioreduction system.

What is claimed is: 
     
       1. A compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
         wherein X is a halogen and m is 2, 4, 5, or 6. 
       
     
     
       2. The compound of  claim 1 , wherein X is Cl and m is 2. 
     
     
       3. A compound having the structure of Formula (II): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         X is a halogen; 
         m is an integer between 2 and 6; 
         each of R 1a  and R 1b  is independently selected from the group consisting of an optionally substituted C 1 -C 12  alkyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted C 2 -C 12  alkenyl, optionally substituted C 2 -C 12  alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or 
         R 1a  and R 1b  together with intervening atoms optionally form a 5-7 membered boron ester ring; and 
         R 2  is selected from the group consisting of an optionally substituted C 1 -C 12  alkyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted C 2 -C 12  alkenyl, optionally substituted C 2 -C 12  alkynyl, optionally substituted aryl, and optionally substituted heteroaryl. 
       
     
     
       4. The compound of  claim 3 , wherein Xis Cl and each of R 1a  and R 1b  is a butyl group. 
     
     
       5. A method of making a compound of Formula (B), comprising the steps of:
 reducing the ketone group of a compound of Formula (A): 
 
       
         
           
           
               
               
           
         
         to form a compound of Formula (B): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is Cl; 
         m is 2; 
         the ketone group in the compound of Formula (A) is reduced using Ru(OAc) 2 ((R)-SegPhos) and methanol; and 
         the compound of Formula (B) is produced in an enantiomeric excess of greater than 99%. 
       
     
     
       6. A method of making a compound of Formula (B), comprising the steps of:
 reducing the ketone group of a compound of Formula (A): 
 
       
         
           
           
               
               
           
         
         to form a compound of Formula (B): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is Cl; 
         m is 2; and 
         the ketone group in the compound of Formula (A) is reduced with an alcohol dehydrogenase system, wherein 
         the alcohol dehydrogenase system comprises a reduced nicotinamide adenine dinucleotide (NADH), a reduced nicotinamide adenine dinucleotide phosphate (NADPH), and an alcohol, 
         the alcohol is isopropyl alcohol, 
         acetone is generated as a by-product, 
         the acetone is removed under vacuum, and 
         the compound of Formula (B) is produced in an enantiomeric excess of greater than 99%. 
       
     
     
       7. A method of making a compound of Formula (C), comprising:
 reacting a boronate compound B(OR 4a )(OR 4b )(OR 4c ) with a compound of Formula (B-1): 
 
       
         
           
           
               
               
           
         
         to form the compound of Formula (C): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is a halogen; 
         m is an integer between 2 and 6; 
         R 2  is selected from the group consisting of, an optionally substituted C 1 -C 12  alkyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted C 2 -C 12  alkenyl, optionally substituted C 2 -C 12  alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; 
         R 4a  and R 4b  are independently selected from the group consisting of an optionally substituted C 1 -C 12  alkyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted C 2 -C 12  alkenyl, optionally substituted C 2 -C 12  alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or 
         R 4a  and R 4b  together with intervening atoms optionally form a 5-8 membered boron ester ring; and 
         R 4c  is selected from the group consisting of an optionally substituted C 1 -C 12  alkyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted C 2 -C 12  alkenyl, optionally substituted C 2 -C 12  alkynyl, optionally substituted aryl, and optionally substituted heteroaryl. 
       
     
     
       8. The method of  claim 7 , wherein X is Cl; m is 2; and R 2 , R 4a , and R 4b  are each independently a butyl group. 
     
     
       9. A method of making a compound of Formula (D), comprising:
 reacting magnesium with a compound of Formula (C): 
 
       
         
           
           
               
               
           
         
         to form a first reaction intermediate; and 
         hydrolyzing the first reaction intermediate to form the compound of Formula (D): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is a halogen; 
         m is an integer between 2 and 6; 
         R 2  is selected from the group consisting of, an optionally substituted C 1 -C 12  alkyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted C 2 -C 12  alkenyl, optionally substituted C 2 -C 12  alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; and 
         each of R 4a  and R 4b  is independently selected from the group consisting of an optionally substituted C 1 -C 12  alkyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted C 2 -C 12  alkenyl, optionally substituted C 2 -C 12  alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or 
         R 4a  and R 4b  together with intervening atoms optionally form a 5-8 membered boron ester ring. 
       
     
     
       10. The method of  claim 9 , wherein Xis Cl; m is 2; and R 2 , R 4a , and R 4b  are independently a butyl group. 
     
     
       11. The method of  claim 9 , wherein the compound of Formula (D) 
       
         
           
           
               
               
           
         
       
     
     
       12. A method of making a compound of Formula (E), comprising
 reducing the ketone group of a keto-ester compound of Formula (A-1): 
 
       
         
           
           
               
               
           
         
         to form a compound of Formula (B-1): 
       
       
         
           
           
               
               
           
         
         reacting a boronate compound B(OR 4a )(OR 4b )(OR 4c ) with the compound of Formula (B-1) to form a compound of Formula (C): 
       
       
         
           
           
               
               
           
         
         reacting magnesium with the compound of Formula (C) to form a first reaction intermediate; 
         hydrolyzing the first reaction intermediate to form a compound of Formula (D): 
       
       
         
           
           
               
               
           
         
       
       and
 reacting the compound of Formula (D) with a complexing agent of Formula (CL): 
 
       
         
           
           
               
               
           
         
         to form the compound of Formula (E): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is a halogen; 
         m is an integer between 2 and 6; 
         n is an integer between 0 and 6; 
         Y 1  is O or N + R 9 R 10 ; 
         Y 2  is O or NR 11 ; 
         R 2  is selected from the group consisting of, an optionally substituted C 1 -C 12  alkyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted C 2 -C 12  alkenyl, optionally substituted C 2 -C 12  alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; 
         R 4a  and R 4b  are independently selected from the group consisting of an optionally substituted C 1 -C 12  alkyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted C 2 -C 12  alkenyl, optionally substituted C 2 -C 12  alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or 
         R 4a  and R 4b  together with intervening atoms optionally form a 5-8 membered boron ester ring; 
         R 4c  is selected from the group consisting of an optionally substituted C 1 -C 12  alkyl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted C 2 -C 12  alkenyl, optionally substituted C 2 -C 12  alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; 
         each R 5  and R 6  is independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C 1-4  alkyl, or R 5  and R 6  together with the atom to which they are attached, form ═O; 
         each R 7  and R 8  is independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C 1-4  alkyl, or R 5  and R 7  together with the atom to which they are attached form an aryl or heteroaryl ring; or R 7  and R 8  together with the atom to which they are attached, form ═O; and 
         each R 9 , R 10  and R 11  is independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C 1-4  alkyl. 
       
     
     
       13. The method of  claim 12 , wherein X is Cl, m is 2, and R 2  is a butyl group. 
     
     
       14. The method of  claim 12 , wherein the complexing agent of Formula (CL) is NH 2 (CH 2 ) 2 OH. 
     
     
       15. The method of  claim 12 , further comprising reacting the compound of Formula (E) with pinanediol to form a compound of Formula (F): 
       
         
           
           
               
               
           
         
         protecting the hydroxy group of the compound of Formula (F) with a PG group to form a compound of Formula (G): 
       
       
         
           
           
               
               
           
         
         reacting the compound of Formula (G) with n-butyllithium and dichloromethane to form a compound of Formula (H): 
       
       
         
           
           
               
               
           
         
         reacting the compound of Formula (H) with an LiN[Si(R 12 ) 3 ] 2  to form a compound of Formula (J): 
       
       
         
           
           
               
               
           
         
         reacting the compound of Formula (J) with R 13 —COCl to form a compound of Formula (K): 
       
       
         
           
           
               
               
           
         
       
       and
 removing the PG group on the compound of Formula (K) to form a compound of Formula (L): 
 
       
         
           
           
               
               
           
         
         wherein: 
         PG is a hydroxy protection group; 
         R 12  is optionally substituted phenyl or optionally substituted C 1-8  alkyl; and 
         R 13  is selected from the group consisting of optionally substituted C 1-8  alkyl, optionally substituted C 0-4  alkyl-C 6-10  aryl, optionally substituted C 0-4  alkyl-5-10 membered heteroaryl, optionally substituted C 0-4  alkyl-C 3-10  carbocyclyl, and C 0-4  alkyl-4-10 membered heterocyclyl. 
       
     
     
       16. The method of  claim 15 , wherein R 13  is